Clinical Trials for PLS

Clinical trial options for PLS are more limited than for ALS — and the honest answer is that this reflects the state of the field rather than any lack of need. But the infrastructure for PLS-specific research is being built, and the opportunities for participation are growing. This page explains what is currently available, why PLS trials are hard to run, and how to find studies you may be eligible for.

The state of PLS clinical research

PLS clinical research in 2026 is in a building phase. For decades, the lack of standardised diagnostic criteria made it impossible to define a consistent PLS patient population for research. Clinical trials require being able to say clearly who is enrolled — and without agreed criteria for what PLS is, that was not possible. The consequence was that PLS-specific trial infrastructure was essentially nonexistent.

That has begun to change. The 2020 consensus diagnostic criteria for PLS provided, for the first time, a standardised definition applicable across research centres internationally. The PLS Natural History Study at Mayo Clinic and Johns Hopkins is generating the prospective natural history data that trial sponsors and regulators need to design and approve future treatment trials. And the validation of the PLS Functional Rating Scale (PLSFRS) as an outcome measure gives researchers a tool to measure what treatment does to PLS progression.

None of this has yet produced an interventional treatment trial for PLS. But the prerequisites for such trials — standardised diagnosis, validated outcome measures, natural history data — are being assembled. Research momentum in PLS is growing; a 2026 review at the International MND Symposium highlighted the application and validation of the 2020 criteria as a key development enabling future research.

Why PLS trials are hard to design

Two features of PLS make clinical trial design genuinely difficult:

Small patient population

PLS represents approximately 1–4% of all motor neuron disease cases. In a disease that is itself rare, this produces a very small pool of potential trial participants. Clinical trials need sufficient numbers to detect a treatment effect statistically — and with PLS, recruiting enough participants for an adequately powered trial is a significant challenge. This is a material reason why industry investment in PLS trials has been limited.

Slow disease progression

PLS progresses slowly — the PLSFRS declines at approximately 0.33 points per month, and functional change is measured over years rather than months. In ALS, the ALSFRS-R drops rapidly enough that a six- to twelve-month trial can detect a treatment effect. In PLS, a trial would need to run much longer — or use very sensitive biomarkers — to detect a slowing of progression. Longer trials are more expensive, logistically harder, and expose participants to more time in an uncertain treatment state.

Neurofilament light chain (NfL) — a biomarker detectable in blood and CSF that reflects neuronal injury — is being investigated as a PLS trial endpoint. Baseline NfL levels have been shown to predict the rate of PLSFRS decline over one year, suggesting NfL could serve as both a prognostic stratification factor and a surrogate endpoint in trials. If validated, this would substantially reduce the required duration of PLS trials.

How the 2020 consensus criteria opened the door

Before the 2020 PLS consensus criteria were published, there was no widely agreed definition of PLS for research purposes. Different research groups used different criteria, making it impossible to pool data across studies or to design a multicentre trial where everyone was enrolling the same patient population.

The 2020 criteria established two levels:

Probable PLS: Progressive pure upper motor neuron syndrome for 2–4 years from onset, with signs in at least two body regions, and no lower motor neuron signs.
Definite PLS: Same as above, but sustained for 4 or more years.

These criteria have since been validated across cohorts in multiple countries. They are now the standard that clinical trials — and the natural history studies supporting them — are built around. Without them, the research infrastructure being built now would not be possible.

The PLS Functional Rating Scale (PLSFRS)

The ALSFRS-R — the standard functional rating scale for ALS — was not designed for PLS. It includes domains (respiratory function, swallowing, nutrition) that are rarely affected in PLS, making it insensitive to PLS-specific functional change.

The PLS Functional Rating Scale (PLSFRS) was developed to address this. It is designed specifically for PLS, focusing on the functional domains most relevant to the disease: limb motor function, balance, speech, and fine motor tasks. It has been validated in the Mayo Clinic PLS Natural History Study and is now the primary outcome measure being used in PLS research.

The existence of a validated, PLS-specific outcome measure is a significant step toward making interventional PLS trials possible. It gives regulators and trial sponsors a tool to measure whether a treatment is actually slowing functional decline.

Active PLS studies

PLS Natural History Study (PNHS)

The PLS Natural History Study is the central ongoing PLS research effort in the United States as of 2026. It is a prospective, multicenter study collecting natural history data and biospecimens from PLS patients at multiple stages of disease.

Sites: Mayo Clinic (Rochester, MN and Jacksonville, FL) and Johns Hopkins. Additional sites may be added as the study expands.

Principal investigators: Dr. Eric Sorenson (Rochester) and Dr. Jaimin Shah (Jacksonville) at Mayo Clinic; Johns Hopkins separately leads a planning and early enrollment component funded through NINDS.

Funding: CDC and ATSDR through the National ALS Registry; additional support from NIH.

What participants contribute: Clinic visits for standardised assessments, blood and CSF samples for biomarker and biorepository purposes, and longitudinal functional tracking using the PLSFRS. This natural history data is the essential prerequisite for future treatment trial design.

Why participate: Even though this is not a treatment trial, participation directly contributes to the evidence base that will make future PLS treatments possible. The study published key results in Annals of Neurology in 2025–2026, including PLSFRS validation and the association between baseline NfL and rate of decline.

How to find it: Search ClinicalTrials.gov for "primary lateral sclerosis natural history" or contact Mayo Clinic's neurology department directly. The Mayo Clinic research page for PLS lists current enrollment status.

UCSD phenotype-genotype-biomarker study

The University of California San Diego (UCSD) is running a study — NCT02327845 — examining phenotype, genotype, and biomarker correlates in ALS and related disorders, including PLS patients. This study focuses on understanding the genetic and biological characteristics that distinguish PLS from ALS and from each other within the PLS population.

This type of research — characterising PLS at the molecular and genetic level — is foundational to identifying potential treatment targets. Without knowing what drives PLS-specific upper motor neuron degeneration, it is difficult to design drugs that would slow or stop it.

NINDS brain function studies

The National Institute of Neurological Disorders and Stroke (NINDS) has supported studies examining brain function in PLS using neuroimaging, including studies of how cortical and subcortical regions change over time. These studies contribute to understanding the neurobiology of PLS beyond the motor cortex — acknowledging that PLS involves more than just the corticospinal tracts — and to identifying imaging biomarkers that might serve as trial endpoints.

Why ALS trials sometimes include PLS patients

Some ALS clinical trials — particularly those studying biological mechanisms rather than testing specific drugs — include patients across the MND spectrum, including PLS. This happens for several reasons:

PLS and ALS share upper motor neuron pathology. Research into corticospinal tract degeneration, cortical hyperexcitability, and neuroinflammation is relevant to both.
Including PLS patients in natural history or biomarker studies provides a "comparison population" that can illuminate what is specific to ALS versus what is common to MND generally.
Platform trials and registry studies benefit from the larger, more diverse MND population that inclusion of PLS patients provides.

Inclusion in an ALS trial does not mean you are being treated as an ALS patient. It means your biology is relevant to a research question that spans the spectrum. Always discuss any trial with your neurologist before enrolling, who can assess whether the specific study is appropriate given your diagnosis and clinical status.

How to find PLS trials

ClinicalTrials.gov (clinicaltrials.gov) is the primary registry for all clinical research in the United States. Search for "primary lateral sclerosis" and filter by recruiting status. Some relevant studies will also appear under "motor neuron disease" or "amyotrophic lateral sclerosis" if they include PLS patients.

Mayo Clinic PLS research page — Mayo maintains a list of PLS-specific clinical trials at their centres. This is the most direct route to finding current enrollment opportunities for the Natural History Study.

ALS Association Trial Finder (trialfinder.als.org) — a patient-friendly interface for finding trials. PLS patients can search and filter; some studies that appear are MND-spectrum studies that include PLS.

Your neurologist: Neurologists at specialised ALS/MND clinics are often aware of active PLS research that is not yet prominent in public registries. Asking directly about trial opportunities is worthwhile at every clinic visit.

CDC National ALS Registry: The Registry connects patients to clinical trial opportunities and is the mechanism through which some PNHS recruitment happens. Enrolling in the Registry (atsdr.cdc.gov/als-registry) keeps you in the pipeline for PLS-relevant research opportunities.

What to ask when considering a trial

Before enrolling in any clinical study, it is worth having clear answers to the following:

Is this a treatment trial or an observational/natural history study? The distinction matters for what you are being asked to do and what benefit — direct or indirect — you might receive.
What are the inclusion and exclusion criteria? Disease duration, diagnostic classification (probable vs definite PLS), functional status, prior medications, and genetic status can all affect eligibility.
What does participation involve? Visit frequency, duration of the study, sample collection requirements, and travel demands.
Is there any direct treatment benefit? For natural history studies, no. For treatment trials, this is the core question — and the honest answer for most early-phase trials is "uncertain."
Can I continue my current treatments while participating? Some trials require washout periods from certain medications.
What happens if my condition changes? What are the provisions for withdrawal or protocol modification if your disease status changes during the study.

Participation in any research is entirely voluntary, and you can withdraw at any time. Discussing any trial with your neurologist before enrolling is always appropriate — they can assess fit with your current clinical situation.

ALS drug pipeline — for context

The ALS drug pipeline is substantially more active than the PLS pipeline, reflecting ALS's larger patient population and research infrastructure. Several agents are in late-stage development that you may encounter in reading about motor neuron disease:

SPG302 (Spinogenix): A synaptogenic compound targeting synaptic density. In Phase 2 ALS trials. Not a PLS trial.
Pridopidine: A sigma-1 receptor agonist with potential neuroprotective effects. In ALS clinical trials. Not a PLS trial.
PrimeC (NeuroSense): A fixed-dose combination of celecoxib and ciprofloxacin. In ALS trials. Not a PLS trial.
Antisense oligonucleotide programs targeting C9orf72, FUS, and ATXN2 — gene-specific approaches for hereditary ALS subtypes. Not PLS trials.

None of these are PLS trials, and none are expected to produce PLS-specific results. They are listed here so that if you encounter them in your reading, you have context for what they are and what they are not. If a genuine PLS interventional trial is initiated, it will be a significant development — and would be added to this page and listed on ClinicalTrials.gov.